Want to learn about scientific topics without needing a PhD? Check out the Science Simplified blog from TESS Research Foundation! Dr. Tanya Brown, PhD, works with researchers to make science accessible and empower rare disease community members with scientific knowledge. Dr. Brown has over a decade of experience in neurodevelopmental research and is currently the Scientific Director for TESS Research Foundation. Please reach out to her at [email protected] if you have questions or comments.
This article was written by Annabeth Loftman, an undergraduate pursuing a neuroscience degree at Mount Holyoke College.
TL;DR — the blood-brain barrier safeguards the brain and spinal cord from unwanted substances, including many helpful medications. Many viruses have found ways to get around the blood-brain barrier, inspiring researchers to use viruses to help develop new treatments. By replacing harmful viral DNA with a healthy gene, the blood-brain barrier allows passage of the virus’s shell to reach into the brain and if all goes well, patients take the treatment, and the viral proteins escort the drug to where it needs to work. A group of viral vectors, Adeno-associated viruses (AAV), particularly AAV9, excel in transporting gene therapy across the blood-brain barrier, offering new treatment options for disorders such as SLC13A5 Epilepsy.
The Blood-Brain Barrier in Therapeutic Development
In our previous Science Simplified post, we talked about the structure and functions of the blood-brain barrier. In this article, we will review what we learned about the blood-brain barrier and discuss how this is relevant when developing new treatments for diseases that affect the brain.
The Basics of the Blood-Brain Barrier
The blood-brain barrier is a biological system that is incredibly important to the protection of the brain and spinal cord (the central nervous system) from any harmful substances. It is formed primarily of the endothelial cells that line blood vessels and is supported by multiple other types of cells such as pericytes and astrocytes.
In this upcoming diagram, we’re looking at a cross section of a small blood vessel in the central nervous system. This is similar to how you might take an apple and cut it in half to look at the layers on the inside.
These cells work together to make it difficult for ions, molecules, and other cells to pass through the blood vessel walls, increasing the level of control the brain has over what makes it through into the tissue – this helps keep our brains healthy. Many substances in the blood will not hurt or will help the rest of the body, but would hurt the brain. This security system ensures that those substances are delivered to the places that they would do good, rather than stick in the brain or spinal cord. Our blood-brain barrier is essential to proper functioning. Without it, our brains would be unable to stay healthy. In some circumstances, however, it can pose an issue. What happens when doctors need to get medications into the brain to treat a disorder? In order to find treatments for many neurological disorders, researchers must first find a way to bypass the defenses of the blood-brain barrier.
Why is the Blood-Brain Barrier Important to Consider During Therapeutic Development?
Unfortunately, the heightened security against unwanted substances entering the central nervous system means that many helpful medications cannot pass through either. The brain is unable to tell if a foreign substance is helpful or harmful, so it simply will not let it through. In order to get a treatment to the place it needs to go, scientists must find a way for it to slip through the blood-brain barrier. This is done through vectors. Vectors are any carrier of a medicine (or disease). You can think of vectors like a delivery truck carrying important cargo to a destination.
Here, we will be discussing viral vectors. These are tools formed by scientists to deliver new genetic material into cells. Many viruses have developed methods to get around or sneak past the blood-brain barrier in order to infect the brain or spinal cord. For example, some types of viruses create protein shields that replicate the look of substances that the brain is willing to let in. The blood-brain barrier buys the disguise, and allows the virus through, where it can then infect the central nervous system.
Researchers study these viruses in an attempt to use the proteins that allow the viruses to sneak through the blood-brain barrier. Researchers remove the viral DNA that makes you sick and replace it with a specific healthy gene. This way, the remaining shell of the virus retains the ability to get the contents through the blood-brain barrier, and the researchers can use the virus’ disguise for good.
This can be used as a gene therapy to treat diseases. Gene therapy is a treatment for some disorders that introduces a healthy portion of a gene to replace a damaged or missing copy. For example, researchers at UT Southwestern add a healthy copy of SLC13A5 to one of these vectors to make an SLC13A5 gene therapy!
Using different viruses creates different vectors, which work with varying degrees of success. If all goes properly, patients take the treatment, and the viral proteins escort the drug to where it needs to work. In order for this method of delivery to succeed, the treatment must:
- Avoid an immune response from the body against the drug or the vector used
- Get through the endothelial cell layer
- Make it past the other biological components of the blood-brain
barrier - Remain undamaged enough to perform its intended function
As you can see, there is a lot required for a viral vector to work well. It is crucial that researchers find the best vector for the job.
How does the Blood-Brain Barrier Relate to Gene Therapy?
You can read more about the concept of gene therapy in a previous Science Simplified article. Viral vectors are one way to deliver gene therapy through the blood-brain barrier and into the brain. In order to be effective, treatment developers must find a virus to use that can move efficiently to the brain tissue without getting waylaid by the blood-brain barrier. When a vector is only so-so at getting through the blood-brain barrier, patients must take a very large amount of the treatment in order to get an adequate amount through into the brain. Unfortunately, too large of a dose can cause negative side effects or be harmful to other systems in the body. Using a vector that can cross the blood-brain barrier easily means that a smaller dose can be taken without reducing the levels in the central nervous system. This leads to fewer harmful effects from the treatment.
Although many viruses are able to get into the central nervous system, not all are viable choices to use for treatment vectors. Efficiency and accuracy are key when developing gene therapies, but many viruses use backdoors or round-about ways of getting into the brain. For example, the rabies virus does infect the central nervous system, but it arrives there by attaching to nerve cells further out in the body and following them all the way back up to the brain, which is not very direct. The challenge then is finding a vector that would work efficiently in order to bring the treatment directly through the blood-brain barrier.
AAV9-SLC13A5 Gene Therapy
Adeno-associated viruses (AAV) are a group of viral vectors that have been found to efficiently carry gene therapy treatments across the blood-brain barrier. They have been effective in treatments for many body parts, but most relevantly, the spinal cord and brain.
Researchers are working to develop AAV capsids – protein shells from viruses that protect their contents – that are able to move efficiently through the blood-brain barrier to deliver their contents to the brain. The capsids ensure that the treatment inside moves to and is released where it is meant to go. Capsids taken from viruses function as the shield or disguise talked about earlier, allowing the treatment to move stealthily through the blood-brain barrier. Think about the coating around a pill that will dissolve once it’s in your stomach – it keeps the medication protected and on course.
AAV9 is one specific type of adeno-associated virus that has proved to be effective in treating some central nervous system disorders. AAV9 is able to efficiently cross the blood-brain barrier and effectively carry functional genetic material to the targeted cells. This makes it a promising treatment option for disorders such as SLC13A5. This is a current field of study, but more and more is being discovered about how this treatment option could function as time goes on.
The team at TESS is learning from gene therapy research and clinical trials in other diseases that affect the brain, and academic and industry teams are collaborating to advance this research into clinical trials.
Conclusion
The blood-brain barrier can make delivery of certain treatments such as gene therapy difficult. However, many viruses have already been doing the work of finding ways to get through the barrier. Researchers are able to copy the virus’ tools and use them in the treatments they are developing, which allows the gene therapy to get where it needs to go. This is an area that is under active study, and will continue to develop.
Sources
Bell, R. D. (2021). Considerations when developing blood–brain barrier crossing drug delivery technology. Handbook of Experimental Pharmacology, 273, 83–95. https://doi.org/10.1007/164_2021_453#DOI
Gene therapy researchers find viral barcode to cross the blood-brain barrier. UNC Health. (2018, February 8). https://news.unchealthcare.org/2018/02/gene-therapy-researchers-find-viral-barcode-to-cross-the-blood-brain-barrier/
Goodspeed, K., Liu, J. S., Nye, K. L., Prasad, S., Sadhu, C., Tavakkoli, F., Bilder, D. A., Minassian, B. A., & Bailey, R. M. (2022). SLC13A5 deficiency disorder: From genetics to gene therapy. Genes, 13(9), 1655. https://doi.org/10.3390/genes13091655
Liu, D., Zhu, M., Zhang, Y., & Diao, Y. (2020). Crossing the blood-brain barrier with AAV vectors. Metabolic Brain Disease, 36(1), 45–52. https://doi.org/10.1007/s11011-020-00630-2
Images were produced using BioRender.com.
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